Project Abstract Degeneration of the intervertebral disc (IVD) is a leading contributor towards back pain, an epidemic that costs billions of dollars in the US. The IVD consists of a proteoglycan(PG)-rich nucleus pulposus (NP) surrounded by a collagenous annulus fibrosus (AF) that together provide support and transmit complex loads. The IVD degenerative cascade involves a multifactorial progression of biological, biochemical, and structural changes that lead to the collapse of the disc structure and to compromised mechanical function. Despite its significant public health impact, the pathophysiology of disc degeneration remains unclear. The accumulation of Advanced Glycation End-products (AGEs) is associated with aging and diabetes. Increased AGEs has also been associated with IVD degeneration. AGEs form through nonenzymatic glycation, where extracellular sugars undergo Maillard rearrangement with amino acids to become protein adducts and crosslinks. AGES are known to impair the mechanical function of matrix proteins. Beyond matrix modifications, AGEs activate the cellular Receptor for Advanced Glycation Endproducts (RAGE), and RAGE signaling perpetuates immune and inflammatory responses. Because the IVD is avascular and has relatively low tissue remodeling, IVD tissues are susceptible to accumulate AGEs. Despite these observations, it is not known whether AGEs or RAGE signaling have a causal role in IVD degeneration. In this R01 application, we will determine the AGEs- and RAGE-mediated events as disease mechanisms for IVD degeneration. Specifically, we will identify the role of AGEs in altering IVD structure and function and define the necessity of RAGE-signaling in AGEs-mediated degeneration. If our hypotheses are supported, this will provide the putative targets to alleviate the degenerative cascade. The combination of in vivo and ex vivo- in vitro approaches will enable us to carefully dissect the systemic effects of high AGE-loads from tissue- specific effects of AGEs. We also will further develop the in vivo contrast-enhanced microCT of the intervertebral disc as a key technological innovation. This approach provides a resolution that significantly advances the current state-of-the-art compared to microMRIs. We believe that the successful completion of the proposed aims will significantly advance our knowledge of intervertebral disc biology and intervertebral disc imaging.